Sustained release formulations of sotalol

ABSTRACT

Sustained release compositions of sotalol, or a pharmaceutically acceptable salt thereof, are provided. In certain examples, sotalol, or a pharmaceutically acceptable salt thereof, may be administered in an effective amount to provide a therapeutic effect to a patient, such as, for example, a patient suffering from a cardiac disorder. In some examples, sotalol combined with a sustained release system may be administered to provide a sustained release of sotalol for a desired period, e.g., at least about 24 hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/134,089, filed May 20, 2005, which claims the benefit under 35 U.S.C.§119(e) to U.S. Provisional Application No. 60/573,367, filed May 20,2004, the entire disclosures of each of which are hereby incorporated byreference herein.

BACKGROUND

For many decades, the clinical significance of prolonged duration ofaction for drugs used in the control of heart disease has beenappreciated. It is recognized that many life-threatening heart disordersoccur in recurrent episodes. This pattern is typified by the attacks ofangina pectoris (chest pain) and especially disorders of heart rhythmsuch as ventricular arrhythmias and in particular atrial fibrillation.Indeed, arrhythmia currently is the most common serious disorder of theheart beat. It is responsible for much morbidity as well as mortality.Thus, drug therapies targeting these conditions require continuous drugaction without periodic or intermittent lapses due to suboptimal drugconcentrations between dosing intervals. There remains a need for betterdrug formulations to control heart disorders.

SUMMARY

In accordance with a first aspect, a sustained release composition ofsotalol, or a pharmaceutically acceptable salt thereof, is disclosed. Incertain examples, an oral solid sustained release composition, which mayrelease sotalol over a time period longer than for conventionalformulations (e.g., 24 hours or more) is provided. In some examples, thecompositions may be ingested orally and may thereby be exposed to one“environment of use,” namely the gastrointestinal tract. In otherexamples, the compositions may be exposed to other “environments of use”(e.g. an aqueous solution of the kind used in in vitro dissolutiontesting). In certain examples, the sustained release compositioncomprises sotalol, or a pharmaceutically acceptable salt thereof, and asustained release system. In some examples, the sotalol, or apharmaceutically acceptable salt thereof is present in an effectiveamount to provide a therapeutic effect in a patient. In certainexamples, the sustained release system may provide sustained release ofsotalol for at least about 24 hours. In some examples, the 24 hourperiod may be any period that is still a sustained period relative toconventional drug activity duration and/or half-life of sotalol. Incertain examples, the sustained release system may be an oral, rectal,topical or parenteral system. In some examples, the sotalol, or apharmaceutically acceptable salt thereof, may be an analog of sotalol, aderivative of sotalol, a mixture of sotalol constituents, an isomer ofsotalol, a racemic mixture of sotalol, or combinations thereof.

In accordance with another aspect, a sustained release composition ofsotalol, or a pharmaceutically acceptable salt thereof, is disclosed. Incertain examples, a sustained release composition of sotalol, or apharmaceutically acceptable salt thereof, comprises an effective amountof sotalol, or a pharmaceutically acceptable salt thereof, to provide atherapeutic effect to a patient. In certain examples, the sustainedrelease composition may also include a sustained release excipientsystem of a heteropolysaccharide gum or a homopolysaccharide gum (orboth) that is capable of cross-linking or being cross-linked. In otherexamples, the sustained release composition may also include an inertpharmaceutical diluent. In yet other examples, the sustained releasecomposition may also include a pharmaceutically acceptable cationiccross-linking agent. In certain examples, the cross-linking agent may becapable of cross-linking with a gum and/or may increase the gel-strengthof the gum when exposed to an environmental fluid or environment of use.In certain examples, the sustained release composition may be effectiveto provide sustained release of sotalol for at least about 24 hours whenexposed to the environmental fluid or the environment of use. In someexamples, the 24 hour period may be any period that is still a sustainedperiod relative to conventional drug activity duration and/or half-lifeof sotalol. In certain examples, the sustained release system may be anoral, rectal, topical or parenteral system. In some examples, thesotalol, or a pharmaceutically acceptable salt thereof, may be an analogof sotalol, a derivative of sotalol, a mixture of sotalol constituents,an isomer of sotalol, a racemic mixture of sotalol, or combinationsthereof.

In accordance with an additional aspect, a method of preparing asustained release composition of sotalol is provided. In certainexamples, the method includes preparing a sustained release compositionof sotalol. The sustained release composition of sotalol may be any ofthe illustrative forms described herein, e.g., an effective amount ofsotalol and a sustained release system. In certain examples, the methodmay further include combining the sustained release composition, or apharmaceutically acceptable salt thereof, with a gum to provide adrug/gum ratio determined to provide a desired degree of sustainedrelease. In some examples, the method may also include tableting thecombined sotalol and gum such that each tablet includes a dose ofsotalol effective to provide a therapeutic effect, e.g., in a humanpatient, for at least about 24 hours.

In accordance with an additional aspect, a method of preparing asustained release composition of sotalol is provided. In some examples,the method includes preparing a sustained release system. In certainexamples, the method may also include combining the sustained releasesystem with a sotalol, or a pharmaceutically acceptable salt thereof.The sotalol may be any of the illustrative forms described herein, e.g.,an effective amount of sotalol, analog or derivative thereof. In certainexamples, the method may further include quantifying the combinedsustained release system and the sotalol into discrete unit forms suchthat each unit, regardless of composition, form, route ofadministration, etc., includes a dose of sotalol effective to provide atherapeutic effect for at least about 24 hours, e.g., effective toprovide a therapeutic effect in a human patient in need of treatment forat least about 24 hours.

In accordance with another aspect, a method of treating a patient with asustained release formulation of sotalol is disclosed. In certainexamples, the method includes administering an effective amount of asustained release dosage form of sotalol, or a pharmaceuticallyacceptable salt thereof, to the patient. In some examples, the methodmay further include preparing a sustained release system. In otherexamples, the method may further include combining the sustained releasesystem with sotalol, or a pharmaceutically acceptable salt thereof. Inyet other examples, the method may further include tableting orproducing units of the combined sustained release system and sotalolsuch that each tablet or unit includes a dose of sotalol effective toprovide a therapeutic effect, e.g., to a patient in need of treatment,for at least about 24 hours.

It will be recognized by the person of ordinary skill in the art, giventhe benefit of this disclosure, that the illustrative sustained releasecompositions described herein represent a significant advance intreatment of certain medical disorders, such as cardiac disorders.Numerous formulations effective to provide sustained release of sotalolfor a selected period will be readily selected by the person of ordinaryskill in the art, given the benefit of this disclosure.

DETAILED DESCRIPTION

Certain features, aspects and examples of the instant technology aredescribed below with reference to certain illustrative examples. It willbe recognized by the person of ordinary skill in the art, given thebenefit of this disclosure, that other features, aspects and examplesmay be included in the illustrative examples described herein.

Throughout this disclosure, the term “sotalol” is often used. This termis intended to refer to various forms, derivatives, isomers, analogs andthe like of sotalol, including but not limited to sotalol hydrochloride,a sotalol derivative, a sotalol analog, a sotalol isomer, a racemicmixture of sotalol form, and the like. In particular, anytherapeutically effective form of sotalol may be used in any of thesustained release compositions disclosed herein in order to achieve asolid or other dosage form with therapeutic properties that include thebenefits of the sustained release formulation described here as well asthe unique benefits, if any, of such derivative, analog, isomer or likeform. Thus, in an exemplary preferred embodiment, one skilled in the artmay employ one of the sustained release formulations and methodsdescribed herein but replace sotalol hydrochloride with any permissiblecombination of D- and L-isomers of sotalol. Such a sustained releaseformulation may not only have the benefits of a 24 hour release but mayalso enjoy the unique benefits of reducing unnecessary beta-blockade.The utilization of the sustained release formulation in this mannerwould allow unprecedented sustained release anti-arrhythmic therapy inpatients with structural heart disease and other such conditions wheresustained release therapy would be optimal provided that beta-blockadecould be reduced. Accordingly, uses of the term “sotalol” throughoutthis document should be understood to include such analogs, derivatives,isomers, racemic mixtures and the like as context permits. Embodimentsof the present compositions produced with such analogs, derivatives,isomers, racemic mixtures, and the like are within the scope of thisinstant technology.

As used herein, the term “treatment” is intended to encompass, amongother things, prophylaxis/prevention, therapy, maintenance, symptomalleviation, and cure. A patient receiving a sustained release sotalolcomposition and/or treatment may be any living animal organism in need,including primates, in particular humans, and other mammals such as, forexample, equines, cattle, swine, sheep, felines, canines, poultry anddomestic pets in general.

As used herein, the term “sustained release” indicates that thetherapeutically active medicament (sotalol) may be released from thecomposition at a controlled rate in such a manner that blood levels(that are still below the toxic levels of the medicament) may bemaintained at therapeutically beneficial levels over an extendedduration of time (e.g., 24 hours or more, thereby providing a singledose, daily dosage formulation.)

As used herein, the term “environmental fluid” in the context of atleast certain examples refers to an environmental fluid in which thetechnology disclosed herein may be properly utilized (e.g.,gastrointestinal fluid or fluid used in in vitro dissolution.) The term“environment of use” has the same meaning unless otherwise clear fromthe context.

As used herein, the term “effective amount” refers to an amount that mayprovide a desired level of treatment or therapy to a patient in need oftreatment for a disease or disorder. For example, an effective amount ofthe composition may produce some desired therapeutic effect (e.g.,reduction of arrhythmia) in at least a sub-population of cells in ananimal at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be recognized by the person of ordinary skill in theart, given the benefit of this disclosure, that an effective amount fora selected patient may not necessarily be an effective amount foranother patient, and that the effective amount selected for a particularpatient may depend, at least in part, on the patient's weight, sex, age,health status, drug tolerance and the like. As used herein, the phrase“therapeutically-effective amount” to that quantity of the activemedicament (e.g., sotalol hydrochloride or a derivative, isomer, analogor the like form of sotalol). Any illustrative dosages mentionedelsewhere in this disclosure, including the common sotalol dosagesmentioned herein, are provided as examples and should not be construedto limit the scope of the technology described herein.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are, inview of reasonable and current medical and pharmacological standards,suitable for use in contact with the tissues of mammals, such as humanbeings, and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, whereby the benefitsassociated with use of such compound, materials, compositions and/ordosage forms outweigh the associated risks in a manner that falls withina reasonable benefit/risk ratio. The phrase “pharmaceutically-acceptablecarrier” as used herein means a pharmaceutically-acceptable material,composition or vehicle, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting a subject compound from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Many such non-toxiccompatible substances may be employed in compositions disclosed hereinand specifically in the case of sustained release formulations.Additional carriers and/or additives, etc. (e.g., those necessary beyondthe carriers, additives, and excipients, etc., necessary for thesustained release formulation itself) will be dictated by the particularmethod and composition used to achieve a particular sustained releaseformulation. The necessity and propriety of additional carriers,additives, excipients, etc., will be readily determined by one skilledand knowledgeable in the art, given the benefit of this disclosure, andoptionally considering, for example, the principal elements of thesustained release composition, the reason for adding the additionalingredient, and the effect it may have on the sustained releasecomposition's intrinsic therapeutic and functional properties.

In accordance with certain examples, there have been several approachesto ensure longer dosing intervals. A first approach is the synthesis ofcompounds that inherently have elimination half-lives exceeding 24hours. An example of this is the drug amiodarone (1) which has anelimination half-life exceeding 24 hours when given intravenously andover 30 days when administered by mouth. A second approach focuses onmarkedly increasing the duration of action through a controlled releasemechanism without altering the elimination half-life whereby the samecumulative daily dose of a short acting drug (that is administeredmultiple times during the day) is administered once daily tocontinuously maintain the tissue and blood levels without significantfluctuations. Such controlled release action is likely to ensurecontinuous protection against recurrences of disorders such asmyocardial ischemia, aberrations of heart rhythm, and abnormal increasesin blood pressure in patients with hypertension.

This second approach, which does not involve altering the normalelimination half-life of drugs, has utilized a wide diversity ofmethods. Various hydrogels, for example have been used in thedevelopment of controlled release medicines, some being synthetic,others semi-synthetic, and others of natural origin, all with variableeffectiveness in controlling and sustaining drug release after oralingestion and thereby prolonging the overall increase in the duration ofdrug action.

In the past, in view of the significant episodic nature of heartdisorders, a major objective was to ensure better patient compliance inadministering drugs acting on the heart and blood vessels. In recentyears, however, there has been an increasing focus on prolonging thetime course of the pharmacodynamic properties of such drugs with thecontinuity of effect over successive dosing intervals. Indeed, this is acritical therapeutic objective in many cardiovascular disordersincluding cardiac arrhythmias that are life-threatening or that areassociated with major morbidities. In this context, the two mostcommonly used drugs in the control of such arrhythmias are sotalol (2)and amiodarone (1).

Although sotalol has been the prototype of the so-called class IIIanti-arrhythmic compounds and its unique electrophysiological propertieswere described in 1970 (2), it is only relatively recently that it hasdrawn widespread attention as an agent for controlling cardiacarrhythmias (3-7). The reasons are several-fold. For one, the CAST trial(8) and various meta-analytic studies of different electrophysiologicalclasses of compounds have indicated the potentially lethal propensity ofsodium-channel blockers when they are used for arrhythmia control inpatients with structural heart disease (6). Moreover, extensiveexperience with the drug amiodarone, widely perceived as also actingprincipally via lengthening cardiac depolarization and by adrenergicinhibition, has contributed to the increasing shift from the use ofclass I to class III agents (9, 10).

Sotalol (3-7, 11-13) and amiodarone (1, 9, 10) have now emerged as thetwo most significant drugs for the control of atrial fibrillation forrestoration and maintenance of sinus rhythm (14). They are also the mostsignificant medicaments for the reduction of defibrillator shocks inpatients in whom implantable devices are placed for the prevention ofsudden cardiac death. However, there are major differences in theoverall properties of the two compounds. On the one hand, sotalol hasthe unique combination of a nonselective beta-blocking property while atthe same time effecting prolongation of cardiac repolarization in theatria as well in the ventricles. Sotalol is 100% bioavailable and has anelimination (exclusively renal) half-life of 8-12 hours (administeredtwice daily). In contrast, amiodarone is structurally andpharmacologically complex, its bioavailability is 30-50%, it ismetabolized in the liver and none is excreted by the kidney. It blocksthe adrenergic receptors nonspecifically rather than at the directreceptor level. When given orally, the drug prolongs repolarization inmost cardiac tissues. Unlike sotalol, amiodarone has a complex patternof often serious adverse reactions and its elimination half-life isexceedingly long. On the other hand, the prolonged half-life ofamiodarone which permits once-daily drug administration, often only 5days per week, has been associated with the continuous maintenance ofsinus rhythm for prolonged periods of time in patients with atrialfibrillation restored to sinus rhythm (10). It is noteworthy thatsotalol is as effective as amiodarone in inducing spontaneous conversionof atrial fibrillation to sinus rhythm, and is equally effective asamiodarone in facilitating direct current cardioversion of atrialfibrillation compared to placebo, thus indicating that the drug exertssimilar anti-fibrillatory effects in the atrial myocardium with respectto the rhythm disorders known as atrial flutter or fibrillation.However, sotalol in conventional doses has been found to besignificantly less effective than amiodarone in maintaining thestability of sinus rhythm in patients with atrial fibrillation restoredto sinus rhythm. It is therefore likely that the very much shorterduration of action of sotalol, as compared to amiodarone, is a cause ofthe lower effectiveness of the drug, since multiple daily doses in thissetting typically result in breakthroughs of the arrhythmia undertreatment. This shortcoming in the overall property of sotalol is likelyto be overcome by the development of a controlled and sustained-releaseformulation for the release of the compound such as, for example, theillustrative sustained release compositions disclosed herein.

There have been a number of patents and publications that relate tosustained and controlled-release formulations for the release ofmetoprolol, a beta-blocker, which, unlike sotalol, does not exhibit anyeffects on cardiac repolarization. Barring the presence of themethylsulphonyl substituent in the para position of the aromatic ring ofthe sotalol molecule, sotalol and metoprolol are very similar inchemical structure. Various controlled and sustained releaseformulations for the release of metoprolol have been described,including in a number of patents: U.S. Pat. No. 5,169,638, U.S. Pat. No.4,792,452, U.S. Pat. No. 4,957,745, U.S. Pat. No. 4,871,549, U.S. Pat.No. 5,081,154, U.S. Pat. No. 4,994,276, U.S. Pat. No. 5,128,143, U.S.Pat. No. 5,135,757 and WO Patent No. 9513055 (entitled “SustainedRelease Formulations For 24 Hour Release of Metoprolol”, hereinafter andfor the purpose of this disclosure only sometimes referred to as the “24Hour Release Metoprolol Patent”), each of which is hereby incorporatedby reference in its entirety for all purposes.

U.S. Pat. No. 5,169,638, and the previously filed U.S. Pat. No.4,792,452, describe a pH-independent controlled release pharmaceuticalformulation in the form of a powder filled capsule, where such powder isbasic in character (e.g. metoprolol). The formulation's principlecomponents are a water-soluble salt of polyuronic acid and apH-independent hydrocolloid gelling agent (such ashydroxypropylmethylcellulose, hydroxypropylcellulose, ormethylcellulose). The formulation, free of calcium ions and carbondioxide producing material, will float in gastric juices, and thusprolong the release of the active powder ingredients.

U.S. Pat. No. 4,957,745 describes a controlled release system formetoprolol that comprises principally a number of beads of metoprololsuch that a polymer membrane permeable to metoprolol (e.g.ethylcellulose or a mixture of ethylcellulose andhydroxypropylmethylcellulose) coats each of the beads. The coating, inprescribed amounts, will enable release of metoprolol over a period ofat least 15 hours nearly independent of the pH in the pH interval 1-8.

U.S. Pat. No. 4,871,549 describes another controlled release system formetoprolol, a so called “Time Controlled Explosion System” whereby aswelling agent (e.g., a low substituted hydroxypropylcellulose, sodiumstarch glycolate or carboxymethylcellulose sodium) and a core of thedrug metoprolol are coated with a water-insoluble coating material(e.g., ethylcellulose). This facilitates controlled release because thewater-insoluble coating ruptures after a definite period of time,commonly referred to as “lag time.” The lag time will depend on therelative amount of water-insoluble coating material present. By mixinglag time systems in a particular sustained release preparation,different sustained and controlled release patterns can be achieved.

U.S. Pat. No. 5,081,154 proposes an oral composition of metoprololsuccinate that is coated with an anionic polymer comprising about 10% toabout 85% by weight and soluble at a pH above 5.5, and about 15% toabout 90% by weight of a water-insoluble polymer from the group ofquaternary ammonium substituted acrylic polymers. The compositionachieves controlled release of the drug in the gastrointestinal tractbelow the upper part of the small intestine. The 24 Hour ReleaseMetoprolol Patent, focuses on a sustained release excipient systemcomprising the active medicament (e.g., metoprolol), bothheteropolysaccharide and homopolysaccharide gums (e.g., xanthan gum andlocust bean gum, respectively), a cross-linking agent (e.g., monovalentor multivalent metal cations, in particular calcium sulfate and sodiumchloride), and an inert diluent (e.g., lactose, dextrose, sucrose, ormixtures thereof or other pharmaceutically acceptable saccharides) suchthat the use of the cross-linking agent with the heteropolysaccharidesand homopolysaccharides results in increased gel-strength and therebyprovides a sustained release of metoprolol in the environment of usethat is suitable for a single dosage, daily administration. The 24 HourMetoprolol Patent which describes this method incorporates by referencerelated methods that are now commercially available under the tradenameTIMERX™ from Edward Mendell, Co., Inc., N.Y. Such methods are describedin U.S. Pat. No. 4,994,276, U.S. Pat. No. 5,128,143 and U.S. Pat. No.5,135,757, which all describe an excipient system that includes ahydrophilic matrix composed of a heteropolysaccharide and apolysaccharide that can cross link the heteropolysaccharide, and aninert diluent. The specific applicability of these commerciallyavailable methods and the formulation of sustained release metoprololwill be discussed in detail below in connection with certain examples ofthe instant sustained release formulation of sotalol.

In accordance with certain examples, for the preparation of suchsustained release sotalol formulations which may be administered topatients on a once-daily basis, or desired longer time interval, certainexamples disclosed herein may use the most appropriate methods that havebeen developed for other compounds (for example, metoprolol) that havebeen introduced into cardiovascular therapeutics. Having recognized thebiochemical similarity of metoprolol and sotalol, and the existence ofsustained release formulations of the former, a preferred embodiment ofthe instant technology may include one or more of the following: asustained release excipient system comprising the active medicament(e.g., sotalol, or derivatives, analogs, isomers, or the like ofsotalol), both hetero- and homo-polysaccharide gums (e.g., xanthan gumand locust bean gum, respectively), a cross-linking agent (e.g.,monovalent or multivalent metal cations, in particular calcium sulfateand sodium chloride), and an inert diluent (e.g., lactose, dextrose,sucrose, or mixtures thereof or other pharmaceutically acceptablesaccharides). The use of the cross-linking agent with theheteropolysaccharides and homopolysaccharides may result in increasedgel-strength and thereby provides a sustained release of sotalol in theenvironment of use that is suitable for a 24 hour, single dosage, dailyadministration. However, other preparations and formulations for thesustained release of sotalol over a 24 hour or longer period will bereadily selected by the person of ordinary skill in the art, given thebenefit of this disclosure.

In accordance with certain examples, and having recognized thebiochemical similarity of metoprolol to sotalol, other methods mentionedabove for providing sustained release of metoprolol may also be adaptedfor the formulation of sustained or controlled release oral dosage formsof sotalol. In this regard, the following may also be embodiments of theinstant technology: (1) a buoyant controlled release system for sotalol(or an analog, isomer, derivative or the like of sotalol) that includesa pH-dependent polymer that is a salt of alginic acid combined with apH-independent hydrocolloid gelling agent and binder with a prescribedweight ratio of such salt to such gel all within the range of 0.1:1 to10:1, for example; (2) a controlled release system for sotalol (or ananalog, isomer, derivative or the like of sotalol) that comprisesprincipally a number of beads of sotalol or the like such that a polymermembrane permeable to sotalol or the like coats each of the beads; (3) a“Time Controlled Explosion System” whereby a swelling agent (e.g., a lowsubstituted hydroxypropylcellulose, sodium starch glycolate orcarboxymethylcellulose sodium) and a core of the drug sotalol are coatedwith a water-insoluble coating material (e.g., ethylcellulose); and (4)an oral composition of sotalol or the like that is coated with ananionic polymer soluble at prescribed pH, and a prescribed amount of awater-insoluble polymer from the group of quaternary ammoniumsubstituted acrylic polymers whereby the composition achieves targetedrelease of the drug in the gastrointestinal tract below the upper partof the small intestine.

In accordance with certain examples, the composition of the presenttechnology may be prepared as pharmaceutically acceptable oral soliddosage forms, such as pills, tablets or capsules. However, as will beexplained in more detail below, other sustained release formulationswhich release sotalol over a time period, preferably of no less than 24hours, which may be given parenterally, topically, or by way of a bodycavity such as the rectum or nose will be readily developed by theperson of ordinary skill in the art, given the benefit of thisdisclosure.

In accordance with certain examples, the present technology is alsorelated to a method of treatment comprising orally (or otherwise)administering the sustained release sotalol to patients, therebyproviding therapeutically effective blood levels of medicament forpreferably at least about 24 hours. Such methods of treatment, involvingonce-daily dosage of a sustained release compositions of sotalol, mayhave a major therapeutic utility in the 24-hour and continuous controlof signs and symptoms of a number of cardiovascular disorders. Suchmethods of treatment would have particular utility in numeroustherapeutic settings (as well as others which may be determined bysomeone skilled in the art, given the benefit of this disclosure)including, but not limited to:

-   -   i) Acute control and prevention of the recurrences of        life-threatening disorders of rhythm such as ventricular        tachycardia and ventricular fibrillation occurring in patients        with coronary artery disease;    -   ii) Prevention of defibrillator shocks in patients with        implantable devices for the prevention of sudden death (15, 16),    -   iii) Termination and prevention of recurrences of atrial        fibrillation and flutter in patients with ischemic heart disease        as well as heart disease of any etiology;    -   iv) Prevention of the occurrences of atrial fibrillation by        prophylactic administration of sustained release sotalol in        patients at high risk undergoing elective cardiac surgery of any        etiology;    -   v) Symptomatic control of angina pectoris in patients still        experiencing chest pain after cardiac surgery, after myocardial        infarction, or patients with coronary artery disease not        amenable to treatment by surgery or angioplasty;    -   vi) Control of systemic systolic and diastolic high blood        pressure for continuous reduction over 24-hours with single dose        of the formulation;    -   vii) Adjunctive therapy for the control of heart rate and atrial        fibrillation in the initial acute stages of hyperthyroidism;    -   viii) Control of atrial fibrillation, myocardial ischemia in the        setting of ischemic heart disease, and hypertension        simultaneously occurring (as it happens in many elderly        patients);    -   ix) Control of fetal tachycardias through sustained release        formulations of sotalol that are suitable for delivery by direct        fetal therapy involving intramuscular or intraperitoneal        injections; and    -   x) Other uses of sotalol that have therapeutic activity for any        purpose.

In accordance with certain examples, sotalol hydrochloride(4′-(2-isopropylaminoethyl-1-hydroxy)methanesulphonanilidehydrochloride, MW [free base]=308.8 [272.4] g/mol) is a nonselectiveadrenoceptor-blocking agent at all doses, and at increasing higher dosesit produces lengthening of cardiac repolarization in the atrial as wellas in ventricular tissues. The drug is a 1:1 racemic mixture of D- andL-sotalol. The beta-blocking activity resides in the L-isomer. The drugis devoid of intrinsic sympathomimetic actions and known to have noeffects on blocking sodium-channel activity in heart muscle. Sotalol isabsorbed 100% after oral ingestion, there being no first-pass hepaticmetabolism and metabolic destruction is negligible. Sotalol is excretedalmost completely by the kidneys; renal impairment increases eliminationhalf-life. The mean elimination half-life is about 12 hours; hence, itis typically administered twice daily in equally divided doses. Theseproperties of the drug have been recognized for the currently knownformulation of sotalol, and the provision for safety in this regard isthe recommendation that patients with a creatinine clearance<60mL/minute are best excluded from sotalol treatment. After theadministration of a dose of current formulation of sotalol, the peakplasma concentration is 2-3 hours. At higher doses of the drug,especially during chronic administration of the short-actingformulation, high peak levels of the drug may lead to proarrhythmicreactions in a small proportion of patients. In contrast, this is lesslikely in the case of sustained and controlled release formulation ofthe drug since following ingestion, the peaks and troughs of plasmalevels are unlikely to occur, thereby ensuring a greater measure ofsafety as well as potentially increased efficacy in the treatment ofarrhythmias such as atrial fibrillation and flutter, and ventriculartachycardia and fibrillation.

In accordance with certain examples, sotalol hydrochloride reduces theoxygen demand of the heart at rest as well as during activity by slowingheart rate and reducing cardiac contractility and blood pressure,effects which are responsible for its ability to reduce myocardialischemia and alleviate angina. Another distinct action of the drug slowsthe conduction down the atrio-ventricular node which will lead to theslowing of the ventricular response in atrial fibrillation and atrialflutter, an effect that is utilized in providing relief from shortnessof breath, palpitations, and dizziness, all of which are due to fastheart rates. The prolonging effect of the drug on cardiac repolarizationin combination with the drug's anti-adrenergic action is responsible forthe beneficial effects on cardiac arrhythmias (17).

In accordance with certain examples, sotalol (also known as Sotacor™,Betapace®, Berlex Pharmaceuticals) is commercially available in theUnited States as the salt, sotalol hydrochloride. It is normallyavailable as tablets of 80 mg, 120 mg, and 160 mg, with recommendeddispensing of each tablet strength twice a day, such that the singledaily initiating dose of a sustained release composition describedherein could be, for example, 160 mg, intermediate dose 240 mg, andhighest dose, 360 mg. In the examples described herein, considerationhas been given as to the choice of the method that will be used in thedevelopment of sustained-release sotalol to increase the time course ofdrug action preferably to 24 hours or longer. In this regard, themethods that have been used in the case of metoprolol, a beta-adrenergicdrug that has similar structural features, are of particular interest.Both drugs are freely soluble in water, have similar free base MW(metoprolol 267.4; sotalol 272.4), have significantly similar molecularstructure, and both drugs are almost completely absorbed, althoughmetoprolol is metabolized with somewhat variable bioavailability.Metoprolol's plasma half-life is in the range of 2.5-9.5 hours and ithas been the active medicament of a number of sustained release methodsand formulations.

In certain examples, it is specifically contemplated that, byutilization of the methods and formulations articulated in the 24 HourRelease Metoprolol Patent, and recognizing the significant biochemicalsimilarity of sotalol and metoprolol, a sustained release formulation ofthe three common dosage forms of sotalol may be achieved by utilizingthe same or highly similar formulations and methods of formulation knownor proposed for metoprolol. In a preferred embodiment, a therapeuticallyeffective amount of sotalol is the active medicament (ranging from a lowdose of 160 mg, an intermediate dose of 240 mg, to a high dose of 360mg, for example, as described above) in a sustained release excipientsystem is provided.

In accordance with certain examples, one or more gums may also bepresent in the compositions disclosed herein. In certain examples, thecomposition may include one or more of a hetero- or homo-polysaccharidegum (e.g., xanthan gum and locust bean gum, respectively), across-linking agent (e.g., monovalent or multivalent metal cations, inparticular calcium sulfate and sodium chloride), and an inert diluent(e.g., lactose, dextrose, sucrose, or mixtures thereof or otherpharmaceutically acceptable saccharides) such that the use of thecross-linking agent with one or more of the heteropolysaccharides andhomopolysaccharides results in increased gel-strength and therebyprovides a sustained release of sotalol in the environment of use thatis suitable for a 24 hour, single dosage, daily administration. For thepurpose of this disclosure, the methods and formulations of the 24 HourRelease Metoprolol Patent and any patents in its legal family areincorporated by reference, including all embodiments, preferred orotherwise, articulated therein, that may be applicable to sotalol forthe reasons stated above. Specifically, as with metoprolol, theheteropolysaccharide for the purpose of this disclosure would be awater-soluble polysaccharide containing two or more kinds of sugarunits, having a branched or helical configuration, and having bothsignificant water-wicking and thickening properties. A preferredpolysaccharide for use in the compositions disclosed herein, as is usedfor the sustained release formulation of metoprolol, is xanthan gum orits derivatives. As with metoprolol, the homopolysaccharide used shouldpreferably be capable of cross-linking with the heteropolysaccharide. Inthis regard, so called galactomannan gums, comprised solely of mannoseand galactose, may be utilized, in particular those which have higherproportions of unsubstituted mannose regions. Locust bean gum is apreferred homopolysaccharide. Moreover, the combination of xanthan gumand locust bean gum is a preferred heteropolysaccharide andhomopolysaccharide combination. Because of the similarity of metoprololand sotalol, the controlled release properties of the sustained releasesotalol formulation involving cross-linked gums may be optimal when theratio of heteropolysaccharide to homopolysaccharide (i.e., galactomannangums) is from 3:1 to about 1:3, with the same preferred ratio at about1:1. Nonetheless, as with the sustained release metoprolol formulation,a sustained release excipient may comprise from approximately 1% toapproximately 99% by weight heteropolysaccharide gum and fromapproximately 99% to approximately 1% by weight homopolysaccharide gum.The person of ordinary skill in the art, given the benefit of thisdisclosure, will be able to select suitable gums, and suitable amountsof the gums, for use in the compositions disclosed herein. As with themetoprolol formulations involving cross-linked gums, the self-bufferingproperties of xanthan gum and other components of the formulation mayallow them to be pH-independent as they move through thegastrointestinal tract and may be substantially impervious to sotalol'ssolubility.

In accordance with certain examples, a cross-linking agent may also bepresent in the compositions disclosed herein. As with the metoprololformulations involving cross-linked gums, certain preferred cationiccross-linking agents may be, for example, calcium sulfate and sodiumchloride. Similarly, and for the same reasons, the cross-linking agentmay be incorporated relative to the sustained release excipient of thepresent compositions in an amount of about 1% to 20% by weight of thesustained release excipient. Similarly, the cross-linking agent may beincluded in an amount approximately 1% to 20% by weight of the finalcomposition. A preferred embodiment, as with metoprolol formulations,will include a cross linking agent that comprises about 10% by weight ofthe sustained release excipient. Additional cross-linking agents will bereadily selected by the person of ordinary skill in the art, given thebenefit of this disclosure.

In accordance with certain examples, a diluent may also be present inthe compositions disclosed herein. As with the metoprolol formulationsinvolving cross-linked gums, an inert pharmaceutical diluent such as,for example, lactose, dextrose, sucrose or mixtures thereof may be used.Moreover, it is conceivable that a hydrophobic material may be added tothe sustained release excipient in such a manner so as to retardhydration of the gums but not disrupt the hydrophilic matrix formed bythe gums when they are in the gastrointestinal tract or otherenvironmental fluid. Suitable diluents for a particular sustainedrelease sotalol composition will be readily selected by the person ofordinary skill in the art, given the benefit of this disclosure.

In accordance with certain examples and referring to tablet productionfor the oral solid dosage form of sotalol derived from a methodanalogous to the methods described in the 24 Hour Metoprolol Patent,sustained release excipients described above can be combined withsotalol and lubricants and then directly compressed, or may be processedinto tablets by conventional wet granulation. More specifically,utilizing the wet granulation methods such as those outlined in the 24Hour Metoprolol Patent, the prescribed amounts of theheteropolysaccharide gum, the homopolysaccharide gum, the cationic crosslinking agent, and the inert diluent may be combined and then subjectedto a moistening agent such as water (or alcohol, or the like). Theresulting moistened mass may then be dried and milled to the desiredparticle size using conventional drying and milling methods employed byone skilled in the pharmaceutical arts. It should be noted that wetgranulation is a preferred method of preparation for the excipient,noting however that any agglomeration technique may be used to produce apharmaceutically acceptable excipient. The resulting sustained releaseexcipient may then be combined with sotalol either by way of aV-blender, by wet granulation or by other suitable methods that will beselected by the person of ordinary skill in the art, given the benefitof this disclosure. Before compression into solid dosage form, apharmaceutically acceptable lubricant may be added; for example,magnesium stearate may be added in an amount of approximately 0.5% toapproximately 3% by weight of the solid dosage form. The commerciallubricant Pruv®, produced by Edward Mendell Co., Inc. (Cedar Rapids,Iowa), may be one preferred lubricant as it is with regards to thepreparation of solid dosage sustained release metoprolol. Additionallubricants for use in the compositions disclosed herein will be readilyselected by the person of ordinary skill in the art, given the benefitof this disclosure.

In accordance with certain examples, hydrophobic materials may beincluded in the compositions disclosed herein to slow hydration. Forexample, hydrophobic materials may slow hydration without disruption ofthe hydrophilic matrix formed by the gums. The hydrophobic material maybe, for example, ethylcellulose or any pharmaceutically acceptablehydrophobic materials known to those skilled in the art. Suchhydrophobic material may be included in the sustained release excipientof the present compositions in an amount from about 1% to about 20% byweight (more preferably from about 3% to about 12%) and most preferablyfrom about 5% to about 10% by weight of the final product.

In accordance with certain examples, a complete mixture of sustainedrelease sotalol formulation resulting from the methods outlined above(and explained in detail in the 24 Hour Metoprolol Patent), providedthat it is enough to make a batch of tablets, may then be processed intotablets using conventional tablet machinery at normal compressionpressure. As with metoprolol, however, care should be taken to ensurethat it is not over-compressed to such an extent that proper hydrationdoes not occur in the presence of gastrointestinal fluid or theenvironmental fluid. Because the molecular weight and structuralsimilarities of sotalol and metoprolol, the expected tablet weights mayrange, for example, from about 300 mg to 950 mg, and the relativeweights of drug to tablet may fall within the range specified in theexamples outlined in the 24 Hour Metoprolol Patent. For instance, in theexamples contained in the 24 Hour Metoprolol Patent, three tablets, eachcontaining 100 mg of metoprolol, were combined with various amounts ofthe gum in drug:gum ratios of 1:1.77, 1:2.57, and 1:3. In all cases, 24hour sustained release was achieved in dissolution tests conducted in anautomated USP dissolution apparatus. In all cases, as the amount of gumin the formulation was increased, the metoprolol release rate decreased,though all achieved release over a 24 hour period. Indeed, subsequenttests showed that increasing the amount of gum even more relative to thedrug resulted in even more prolonged release beyond 24 hours. Similarly,removal of the hydrophobic material (ethylcellulose) from the excipientmixture also resulted in even more prolonged release beyond 24 hours.And finally, tablet size did not appear to affect the release rates.

In accordance with certain examples, recognizing the biochemicalsimilarity of metoprolol and sotalol, and given that it is recognizedthat sotalol will not interact substantially differently with theexcipients, the ratios and methods outlined above and in more detail inthe 24 Hour Metoprolol Patent may be suitably adapted for formulationand production of a sustained release (preferably 24 hours or longer)compositions of sotalol. Also, additional and/or alternative methods forpreparing the compositions disclosed herein may be found, for example,in U.S. Pat. No. 5,169,638, U.S. Pat. No. 4,792,452, U.S. Pat. No.4,957,745, U.S. Pat. No. 4,871,549, and U.S. Pat. No. 5,081,154, theentire disclosure of each of which is hereby incorporated herein byreference for all purposes. For example, a buoyant controlled releasepharmaceutical powder formulation of sotalol may be produced utilizingthe methods articulated in U.S. Pat. No. 5,169,638 (also articulated inrelated form in U.S. Pat. No. 4,792,452.), particularly in view of thesimilarities between sotalol and metoprolol and particularly in view ofthe fact that such powder formulation was particularly adapted forcontrolled release powder-filled capsules containing metoprolol in itstartrate form. We expect that the amount of sotalol present in thecompositions disclosed herein would be 75% by weight, and preferentiallyup to about 60% by weight. Suitable amounts of sotalol to provideeffective amounts in the sustained release compositions disclosedherein, will be readily selected by the person of ordinary skill in theart, given the benefit of this disclosure.

In accordance with certain examples, the composition may also includeother components, such as, for example, a water-soluble salt ofpolyuronic acid (e.g., forms high in guluronic acid as sourced fromLaminaria digitata, forms high in manuronic acid as derived fromAscophyllum nodosum, and other sources) and a pH-independenthydrocolloid gelling agent (such as hydroxypropylmethylcellulose,hydroxypropylcellulose, or methylcellulose). The compositions disclosedherein, free of calcium ions and carbon dioxide producing material(s),may float in gastric juices, and thus prolong the release of the activepowder ingredients. The amount of salt of the polyuronic acid willdepend on the amount of drug present, with illustrative amounts ofpolyuronic acid being present in an amount ranging from about 15% to 45%by weight composition, more particularly from about 20% to 40% by weightof the composition. An alginic acid salt is preferred (e.g., potassiumalginate, ammonium alginate, and preferably sodium alginate). Thehydrocolloid gelling agent may be included in an amount up to 35% byweight of the formulation, and the polyuronic acid salt to hydrocolloidgelling agent weight ratio may be from about 0.1:1 to about 10:1, andmore particularly from about 0.4:1 to about 8:1. It should also be notedthat the hydrocolloid gel, which may be desirable to include in certaincompositions, may be used to provide a viscosity of 50 to 100,000 cPs ina 2% aqueous solution at 20 degrees C. and may have a molecular weightranging from 80,000 to 300,000.

In accordance with certain examples, the compositions disclosed hereinmay be prepared in a controlled release preparation involving a numberof beads having a soluble component comprising at least about 95%weight/weight of a salt of sotalol and a sotalol permeable polymericmembrane coating enveloping each of the beads. The coating may beethylcellulose or a mixture of ethylcellulose andhydroxypropylmethylcellulose. In some examples, the coating may bepresent in amounts such that the sotalol is released through the coatingover a period of at least 15 hours virtually independent of pH (in theinterval pH 1-8). This method is described in detail with regards tometoprolol in U.S. Pat. No. 4,957,745. Recognizing the biochemicalsimilarities of metoprolol and sotalol, the formulation delineated formetoprolol may be used to easily determine the formulation of a longacting sustained release formulation of sotalol. To achieve such aformulation, sotalol beads may be formed using the following method asadapted from U.S. Pat. No. 4,957,745: in a fluidized bed granulator,sotalol hydrochloride may be sprayed onto the cores of silicon dioxidefrom a solution of ethanol 95%. The beads or granules which are formedmay be covered with the polymeric layer containing ethyl cellulose,hydroxypropylmethyl cellulose and acetyltributylcitrate by applying(through spraying or similar methods) a solution of such substances inmethylene chloride and isopropylic alcohol. The coated beads may then befilled or packed into hard gelatin capsules. Variations on the method toachieve a desired configuration, outlined in U.S. Pat. No. 4,957,745with regards to metoprolol, may employ addition of other additives aswell as magnesium-stearate (0.1%), and coating of the tablets in acoating pan.

In accordance with certain examples, another method which may be adaptedto preparation of sustained release sotalol compositions is the “TimeControlled Explosion System”, outlined in U.S. Pat. No. 4,871,549,whereby a swelling agent (e.g., low substituted hydroxypropylcellulose,sodium starch glycolate or carboxymethylcellulose sodium) and a core ofthe drug sotalol may be coated with a water-insoluble coating material(e.g. ethylcellulose). The ratio of the drug and the swelling agent inthe beads or granules will be readily selected by the person of ordinaryskill in the art, given the benefit of this disclosure. Where thedesired form is tablet, such oral dosage form may be prepared accordingto conventional procedure by compressing the mixture of sotalol,swelling agent, diluents and lubricants (e.g., magnesium stearate,etc.). The ratio of the drug and the swelling agent in the tablet mayvary depending on the drug and other additives used, and may bedetermined by one skilled in the art of pharmaceutical preparation usingthe methods outlined above and in more detail in U.S. Pat. No.4,871,549. The sustained release pattern for a particular preparation ofsotalol may be determined by one skilled in the art of pharmaceuticalpreparation by adjusting the amount of water-insoluble coating materialused and/or by utilizing a method of mixed “lag time” systems in aparticular preparation as explained in detail in U.S. Pat. No.4,871,549.

In accordance with certain examples, another method which may be used toproduce a sustained release formulation of sotalol may be adapted fromthe method outlined in U.S. Pat. No. 5,081,154, where an oralcomposition of metoprolol succinate is coated with a layer comprisingabout 10% to about 85% by weight of an anionic polymer soluble at a pHabove 5.5, and 15 to 90% by weight of a water-insoluble polymer from thegroup of quaternary ammonium substituted acrylic polymers. Thecomposition may achieve targeted release of the drug in thegastrointestinal tract below the upper part of the small intestine.Recognizing the biochemical similarity of sotalol and metoprolol, asustained release formulation may be achieved by applying a similaranionic polymer coating. As proposed with metoprolol succinate, a splitdose unit of sotalol may achieve prolonged steady blood plasma levels byadministering such a dose with some of the therapeutically activemedicament particles having the coating and some of the therapeuticallyactive medicament particles not having the coating. The person ofordinary skill in the art, given the benefit of this disclosure will beable to design suitable spit dose compositions including sotalol.

In accordance with certain examples, other methods and formulations,using other excipient systems, carriers, and/or additives, which achievethe sustained release properties described herein and/or which enablethe treatment regimen(s) described herein, will be determined by oneskilled and knowledgeable in the art, given the benefit of thisdisclosure, and are within the scope of the present technology. Inparticular, there are multiple embodiments, configurations and examplesof the instant technology which may include the elements of a sustainedrelease excipient system (e.g., the formulations and methods describedin the 24 Hour Release Metoprolol Patent), the therapeutically-activemedicament (sotalol hydrochloride, or its derivative, analog, isomer orthe like), and certain other elements desirable to provide a sustainedrelease composition. In many cases, the once-a-day or sustained releasedosage of sotalol described herein may be pharmaceutically acceptablecompositions which comprise a therapeutically-effective amount ofsotalol formulated together with one or more pharmaceutically acceptablecarriers, additives, and/or diluents, which may be in addition to thepharmaceutically acceptable excipient system used in the sustainedrelease compositions. Such other carriers, additives and/or diluents maybe for other purposes such as minimization of side effects, sweeteningor taste modification, etc., or may enhance the sustained releaseformulation in some manner. The pharmaceutical compositions disclosedherein may be specially formulated for administration in solid or isliquid form through various delivery routes, including but not limitedto those used, modified, and/or adapted for the following: (1) oraladministration, including but not limited to drenches (aqueous ornon-aqueous solutions or suspensions), tablets, boluses, powders,granules, pastes for application to the tongue; (2) topical application,including but not limited to a cream, ointment or spray applied to theskin; (3) intravaginally or intrarectally, including but not limited toa suppository, pessary, cream or foam; (4) nasally; or other suitableadministration methods that will be readily selected by the person ofordinary skill in the art, given the benefit of this disclosure.

In accordance with certain examples, the compositions disclosed hereinmay be suitable for oral, nasal, topical (including buccal andsublingual), rectal, vaginal and/or parenteral administration. Theformulations may be presented in convenient unit dosage form and may beprepared by any suitable methods known to one skilled in the art ofpharmacy. The therapeutically-active quantity of medicament (e.g.sotalol hydrochloride) which can be combined with a carrier material orsustained release excipient system to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration, and other circumstances surrounding the objectives andsubject of the treatment. The amount of medicament which can be combinedwith a carrier material or sustained release excipient system to producea single dosage form will generally be that amount of the compositionwhich produces a therapeutic effect. As with certain preferred exemplaryembodiments described above (i.e. the sustained release excipient systemdescribed in the 24 Hour Release Metoprolol Patent as applied tosotalol), the amount of active medicament (e.g. sotalol) and the amountof excipient material, as well as the proportion of one excipientrelative to another (e.g. the amount of heteropolysaccharide gumrelative to the amount of homopolysaccharide gum relative to the amountof cross linking agent and inert diluent) may be determined by a host offactors, including the desired sustained release, required dosagelevels, minimization of side effects, etc.

In accordance with certain examples, sustained release compositionsadapted and suitable for oral administration may be in multiple formsincluding, but not limited to: (1) capsules, cachets, pills, tablets,lozenges (using a flavored basis), powders, granules, (2) a solution ora suspension in an aqueous or non-aqueous liquid, (3) an oil-in-water orwater-in-oil liquid emulsion, (4) an elixir or syrup, (5) pastillesand/or as mouth washes and the like. The compositions disclosed hereinmay also be administered as a bolus, electuary or paste. In certainexamples, in solid dosage forms suitable for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), itis possible that the sustained release formulation of sotalol may bemixed with one or more pharmaceutically-acceptable additionalingredients including but not limited to: (1) fillers or extenders, (2)binders, (3) humectants, (4) disintegrating agents; (5) solutionretarding agents, (6) absorption accelerators, (7) wetting agents, (8)absorbents, (9) lubricants, and (10) coloring agents. In the case ofcapsules, tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents, though it should be noted that certainexcipient systems, such as the one proposed by the 24 Hour ReleaseMetoprolol Patent, may exhibit self-buffering and thus may be apH-independent formulation. Solid compositions, similar in nature, mayalso be employed as fillers in soft and hard-filled gelatin capsulesusing excipients that may include, but are not limited, to lactose ormilk sugars, high molecular weight polyethylene glycols, and othersimilar materials.

In accordance with certain examples, a tablet may be made by compressionor molding, optionally with one or more accessory ingredients, and byother methods which will be selected by one skilled in the art, giventhe benefit of this disclosure. Compressed tablets may be prepared usinga variety of agents, including but not limited to a binder, a lubricant,an inert diluent, a preservative, a disintegrant, a surface-active agentor a dispersing agent. Molded tablets may be made in a variety of waysknown to one skilled in the art, including but not limited to methodsthat utilize a suitable machine to mold a mixture of the powderedcomposition moistened with an inert liquid diluent. The suitability ofthe method for tablet production may depend, for example, on theprincipal ingredients for the sustained release formulation

In accordance with certain examples, the tablets, and other solid dosageforms of the pharmaceutical compositions disclosed herein, such asdragees, capsules, pills and granules, may optionally be scored orprepared with coatings and shells, including but not limited to entericcoatings and other such layering, coverings and coatings well known inthe pharmaceutical-formulating art. They may also be formulated so as toprovide additional features of controlled release, beyond the sustainedrelease property that is a principal characteristic of the compositionsdisclosed herein. For example, a composition may be designed such thatit releases the active ingredient(s) (e.g., sotalol) only, orpreferentially, in a certain portion or portions of the gastrointestinaltract. Variations in the compositions disclosed herein will be readilyselected by the person of ordinary skill in the art, given the benefitof this disclosure.

In accordance with certain examples, liquid dosage forms for oraladministration of the compositions disclosed herein include, but are notlimited to, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups, elixirs and the like. The liquid dosageforms may contain inert diluents commonly used in the art, including,but not limited to, water or other solvents, solubilizing agents andemulsifiers, and mixtures thereof.

In accordance with certain examples, oral compositions may also includeadjuvants including, but not limited to, wetting agents, emulsifying andsuspending agents, sweetening, flavoring, coloring, perfuming andpreservative agents. Suspensions, in addition to the active compoundsand formulations, may contain suspending agents and the like.Formulations of the pharmaceutical compositions for rectal or vaginaladministration may be produced in a number of forms, including but notlimited to suppositories, which may be prepared by mixing one or morecompositions (e.g., the sustained release formulation including theactive medicament sotalol) with one or more suitable pharmaceuticallyacceptable excipients such as cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and that is/are solid at roomtemperature, but liquid at body temperature, and thus suitable forstorage outside the body and insertion/release/and dispersion in theappropriate body cavity such as the vagina or rectum. Compositionsdisclosed herein that are suitable for vaginal administration may alsoinclude but are not limited to pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate. Dosage forms for the topical or transdermaladministration of a compositions disclosed herein may include but arenot limited to powders, sprays, ointments, pastes, creams, lotions,gels, solutions, patches and inhalants. The active compounds in thecomposition may be combined under sterile conditions with apharmaceutically-acceptable carrier or vehicle, and with anypreservatives, buffers, propellants or the likes which may be desired.The ointments, pastes, creams and gels may include, in addition to anactive compound, other excipients, which may include but are not limitedto: animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.Powders and sprays can contain, in addition to a compound, otherexcipients which may include but are not limited to lactose, talc,silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures thereof. Sprays may also contain propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,that are standard and customary (as determined by current industrystandards) for the production of such materials.

Transdermal patches which deliver the compositions disclosed herein maybe produced by dissolving or dispersing the sustained releaseformulation in the proper medium, which medium would be known by someoneskilled in the art of such preparations. Absorption enhancers may alsobe utilized to maximize and enhance the transdermal delivery of thecomposition where appropriate. The rate of such transdermal flux can becontrolled by a number of ways, including the provision of a ratecontrolling membrane or dispersion of the sustained release compositionin a polymer matrix, gel, or the like.

It should be noted that while unprecedented sustained releaseformulations of sotalol in oral dosage form have been described herein,injectable solutions and intravenous delivery may also be utilized toeffect sustained release sotalol treatment of preferably 24 hours ormore. Injectable depot forms of the compositions disclosed herein, whichmay be rate controlled, may be made by forming microencapsulatedmatrices of the active medicament in biodegradable polymers or byembedding the active medicament in liposomes or microemulsions that maybe safely and effectively used with body tissue. The rate control maydepend, at least in part, on the ratio of drug to polymer, and thenature of the particular polymer utilized.

In accordance with certain examples, it is possible that thepreparations and formulations disclosed herein may be given throughvarious administration routes including but not limited to oral,topical, and rectal. In all cases, they should be given in formssuitable (from a safety and efficacy standpoint) for each administrationroute. However, any alternate forms of delivery or administration,including but limited to those outlined above, are feasible. It shouldalso be noted that the various methods, preparations, compositions, andmodes of delivery and administration discussed above would be consideredand specifically determined by one skilled in the art of pharmaceuticalpreparations, and the method for using the sustained releaseformulations (including the preparations, compositions, modes ofdelivery, administrations, etc.) contemplated in a therapeutic settingwill require consideration of the normal range of factors known to oneskilled in the medical arts.

In accordance with certain examples, actual dosage levels of sotalol inthe pharmaceutical compositions disclosed herein may be adjusted to alevel effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient. The selected dosage level will depend upon avariety of factors including but not limited to the activity of theparticular composition employed, or the ester, salt or amide thereof,the route of administration, the time of administration, the rate ofexcretion of the particular composition being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular composition employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known to one ordinarilyskilled in the medical arts. It is contemplated that sustained releasesotalol may be administered to humans and other animals for therapy byany suitable route of administration, including but not limited toorally, nasally (e.g., by spray), rectally, intravaginally,intracisternally and topically (e.g., by powders, ointments or drops),buccally and sublingually. Irrespective of the route of administrationused, the compositions disclosed herein may be formulated intopharmaceutically-acceptable dosage forms by conventional methods knownto those of skill in the art of pharmaceutical preparations.

In accordance with certain examples, a physician or veterinarian havingordinary skill in the art can, using ordinary skill, determine andprescribe an effective amount of the sustained release compositiondesired. The compositions disclosed herein (i.e., the sustained releaseformulations) may be formulated for administration in any convenient wayfor use in human or veterinary medicine, by analogy with otherpharmaceuticals.

In accordance with certain examples, it is possible that the molecularstructure of sotalol may be altered slightly in the synthesis of thesustained release formulations contemplated by the present disclosure.Such alterations may be desirable to enhance the interaction of themedicament with the other components of the sustained releaseformulation (e.g., the sustained release excipient system) or for othertherapeutic and functional reasons. Such alterations, in addition to theuse of sotalol analogs and derivatives as described above, are withinthe scope of this technology.

In accordance with certain examples, wetting agents, emulsifiers andlubricants, as well as coloring agents, release agents, coating agents,sweetening, flavoring and perfuming agents, preservatives andantioxidants may also be present in the compositions disclosed herein.Additional agents, additives and the like will be readily selected bythe person of ordinary skill in the art, given the benefit of thisdisclosure.

The numbers used in parentheses throughout the disclosure refer to thefollowing citations:

-   1. Singh B N, Vaughan Williams. The effect of amiodarone, a new    anti-anginal drug, cardiac muscle. Brit J Pharmacol 1970; 39;    657-667;-   2. Singh B N, Vaughan Williams E M. A third class of anti-arrhythmic    action. Effects on atrial and ventricular intracellular potentials,    and other pharmacological actions on cardiac muscle, of MJ 1999    (sotalol) and AH 3474. Br J Pharmacol 1970; 39:675-687;-   3. Singh B N: Antiarrhythmic action of dl-sotalol in ventricular and    supraventricular arrhythmias. J Cardiovasc Pharmacol 2:590, 1992-   4. Singh B N: A Symposium: Controlling cardiac arrhythmias with    sotalol, a broad-spectrum antiarrhythmic with beta-blocking effects    and class III activity. Am J Cardiol 65:1A-84A, 1990;-   5. Anderson J L: Sotalol in life-threatening ventricular    arrhythmias: A unique class III antiarrhythmic. Amer J Cardiol    72:1A-80A, 1993;-   6. Singh B N. Current antiarrhythmic drugs: An overview of    mechanisms of action and clinical utility. J Cardiovasc    Electrophysiol 1999; 10: 283-301;-   7. Singh B N. Sotalol: Current status and expanding indications. J    Cardiovasc Pharmacol Therapeut 1999; 4 (1): 59-65;-   8. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators:    Preliminary report: Effect of encainide and flecainide on mortality    in a randomized trial of arrhythmia suppression after myocardial    infarction. New Eng J Med 321:406, 1989;-   9. Singh B N: Antiarrhythmic actions of amiodarone: A profile of a    paradoxical agent. Amer J Cardiol 1996; 78: 41-53;-   10. Singh B N (Ed). A Symposium: Approaches to Controlling Cardiac    Arrhythmias: Focus on Amiodarone, the last 15 Years. Am J Cardiol    1999; 84 (Supp 9A); 1R-174R;-   11. Kato R, Yabek L, Ikeda N, Kannan R, Singh B N.    Electrophysiologic effects of dextro- and levo-isomers of sotalol in    isolated cardiac muscle and their in vivo pharmacokinetics. J Am    Coll Cardiol 1986; 7:116-126;-   12. Antonaccio M J. Gomoll A W Pharmacology, pharmacodynamics and    pharmacokinetics of sotalol. Am J Cardiol 1990; 65:12A-20A;-   13. Nademanee K, Feld G, Hendrickson J A, Singh P N, Singh B N:    Electrophysiologic and antiarrhythmic effects of sotalol in patients    with life-threatening ventricular tachyarrhythmias. Circulation    1985; 72:555-564;-   14. Benditt D G, Williams J H, Jin J et al. for the dl-Sotalol    Atrial Fibrillation/Flutter Study Group. Maintenance of sinus rhythm    with oral dl-sotalol therapy in patients with symptomatic atrial    fibrillation and flutter: A dose-response study. Am J Cardiol 1999;    84:270-176;-   15. Pacifico A, Hohnloser S, Williams J H et al for the d,l-sotalol    implant able cardioverter-defibrillator study group. N Eng J Med    1999; 340: 1855-1862;-   16. Movsowitz C, Marchlinski F E. Interactions between implantable    cardioverter-defibrillators and class III antiarrhythmic drugs. Am J    Cardiol 82:411, 1998; and-   17. Singh B N, Sarna J S M. Mechanisms of action of antiarrhythmic    drugs relative to the origin and perpetuation of cardiac    arrhythmias. J Cardiovasc Pharmacol Therapeut 2001; 6(1):69-87.    Each of the patents and citations listed herein is incorporated    herein by reference in its entirety for all purposes. Should the    meaning of any term in the patents or citations incorporated by    reference conflict with the meaning of any term used in this    disclosure, the meaning of the term in this disclosure is intended    to be controlling.

When introducing elements of the examples disclosed herein, the articles“a,” “an,” “the” and “said” are intended to mean that there are one ormore of the elements. The terms “comprising,” “including” and “having”are intended to be open ended and mean that there may be additionalelements other than the listed elements. It will be recognized by theperson of ordinary skill in the art, given the benefit of thisdisclosure, that various components of the examples can be interchangedor substituted with various components in other examples.

Although certain features, aspects, examples and embodiments have beendescribed above, additions, substitutions, modifications, andalterations of the disclosed illustrative features, aspects, examplesand embodiments will be readily recognized by the person of ordinaryskill in the art, given the benefit of this disclosure.

What is claimed is:
 1. A sustained release composition comprising: aneffective amount of a racemic mixture of D-sotalol and L-sotalol, or apharmaceutically acceptable salt thereof; and a sustained releasesystem, whereby the sustained release system is at least one of atopical, rectal, oral and parenteral system, and is effective to providesustained release of the racemic mixture of D-sotalol and L-sotalol orthe pharmaceutically acceptable salt thereof for at least about 24 hourswhen exposed to an environmental fluid, and wherein such sustainedrelease composition is for use in the treatment of arrhythmia withreduced beta-blockade and for lengthening cardiac repolarization.
 2. Thesustained release composition of claim 1, wherein the sustained releasesystem is at least one of a rectal and oral system.
 3. The sustainedrelease composition of claim 1, wherein the 24 hours is any other periodthat is a sustained period relative to conventional drug activityduration and/or half-life of the racemic mixture of D-sotalol andL-sotalol.
 4. A sustained release composition comprising: an effectiveamount of a racemic mixture of D-sotalol and L-sotalol, or apharmaceutically acceptable salt thereof; a sustained release excipientsystem of a heteropolysaccharide gum or a homopolysaccharide gum that iscapable of cross-linking; an inert pharmaceutical diluent; and apharmaceutically acceptable cationic cross-linking agent capable ofcross-linking with the gums and increasing the gel-strength of the gumswhen exposed to an environmental fluid or environment of use, wherebythe sustained release composition is effective to provide sustainedrelease of the racemic mixture of D-sotalol and L-sotalol or thepharmaceutically acceptable salt thereof for at least about 24 hourswhen exposed to the environmental fluid or the environment of use, andwherein such sustained release composition is for use in the treatmentof arrhythmia with reduced beta-blockade and for lengthening cardiacrepolarization.
 5. The sustained release composition of claim 4, whereinthe 24 hours is any other period that is still a sustained period oftime relative to conventional drug activity duration and/or half-life ofthe racemic mixture of D-sotalol and L-sotalol.
 6. The sustained releasecomposition of claim 4, wherein the sustained release excipient systemis at least one of a topical, rectal, oral and parenteral system.